We request five years of continued support for the longitudinal study of 205 initially late-middle-aged, cognitively normal persons with two copies, one copy and no copies of the apolipoprotein E 54 allele, a common late-onset Alzheimer's disease (AD) susceptibility gene. During the next funding period, 1) we will continue to characterize and compare baseline measurements and longitudinal changes in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), magnetic resonance imaging (MRI) measurements of gray matter density, cortical thickness and whole brain volume, clinical ratings and neuropsychological tests every two years in 35 54 homozygotes, 50 54 heterozygotes, and 75 54 non-carriers, further characterize their relationship to 54 gene dose, and determine the extent to which baseline brain-imaging measurements and longitudinal changes predict subsequent rates of cognitive decline and conversion to mild cognitive impairment (MCI) or probable AD; and we will continue to characterize and compare the same measurements in 15 54 carriers and 30 54 non-carriers from the Latino community to further establish the extent to which our findings are relevant to this understudied minority group. 2) We will also acquire PET measurements of the Pittsburgh Compound B Distribution Volume Ratio (PIB DV) every two years, providing a unique opportunity to detect and track the some of the earliest fibrillar amyloid deposition in cognitively normal persons at three levels of genetic risk for late-onset AD, characterize the relationship of fibrillar amyloid deposition to the other brain imaging changes in these individuals, and ultimately determine the extent to which fibrillar amyloid deposition, alone or in combination with other brain imaging measurements, predicts subsequent rates of cognitive decline and conversion to MCI and probable AD. 3) We will use our proposed presymptomatic brain-imaging endophenotype to evaluate putative modifiers of AD risk, including an aggregate genetic risk score and individual single nucleotide polymorphisms (SNPs) that we have implicated in an independently funded 500,000 SNP whole-genome association study of more than a thousand clinically and neuropathologically characterized AD cases and controls. 4) We will further refine, test and establish the value of advanced voxel-based image-analysis techniques in the unusually early detection and tracking of brain changes associated with the differential risk of AD. 5) Finally, we will continue to share our core resource of DNA, biological specimens, data and findings in support of other investigators and other studies. This study is ultimately intended to provide a cost-effective way to evaluate promising treatments for the primary prevention of AD. Indeed, we have established a new non-profit institute for this very purpose.